DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claim 1, in the paper of 6/18/2026, is acknowledged. Applicants' arguments filed on 6/18/2026, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 1-19, 21 and 22 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Group 1, claims 1-10, 13, 17, 18, to a protease variant, in the paper of 11/11/2025, is acknowledged. Applicant's election without traverse of the following species:
Species Group 1: X215K.
Species Group 2: X99F,X101 L, and X215K.
Species Group 3: X76D, X209W, L262E (X262E).
Species Group 4: X9E, X43R, X76D, X99F, X101L, X103T, X1041, X2051, X206L, X209W, X215K, X259D, X261W, and X262E.
Species Group 5: X97D.
Species Group 6: X161R.
Species Group 7: polyester degrading activity,
in the paper of 11/11/2025, is acknowledged
Claims 9, 10, 11, 12, 14-16, 19, 21 and 22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 1-8, 13, 17 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection was stated in the previous office action as it applied to previous claims 1-8 and 13. In response applicants have amended claim 1 and traverse the rejection as it applies to newly amended claims Claim(s) 1-8, 13, 17 and 18. Claims 17 and 18, which were left out of the previous rejection due to a typographical mistake, are included for the same reasons stated for claim 1 from which they depend.
Applicants traverse the rejection on the basis that applicants submit that the examiner’s rejection is based on the characterization of the claims as reciting all variants with a broad range of sequence identity to SEQ ID NO: 1, where the possesses particular recited substitutions and particular activity. Applicants submit that the claims do not recite all variants with 60% identity to less than 100% identity to SEQ ID NO: 1, but recite all such variants that possess the further recited structural (sequence identity + specific positional modifications) and functional (polyester degrading activity) characteristics. The scope of the variants is materially limited by such structural and functional recitations.
Applicants submit that it is well established that “[t]o satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” (MPEP 2163, citing Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.) It is respectfully submitted that the specification of the present application possesses such description of the claimed variants.
Applicants submit that the examiner’s attention is respectfully drawn to the following relevant law on the written description requirement of 35 U.S.C. § 112 first paragraph, as declared by the Federal Circuit. “The specification need not describe the claimed subject matter in exactly the same term[s] as used in the claims; it must simply indicate to persons skilled in the art that as of the [filing] date the applicant had invented what is now claimed.” Eiselstein v. Frank, 52, F.3d 1035, 1038, 34 USOQ2d 1467, 1470 (Fed. Cir. 1995). Further, with regard to the biochemical arts, the Federal Circuit has held that, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met ... even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure .” (emphasis added) Falkner v. Inglis,448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006).
Applicants submit that the presently claimed variants are recited by structural characteristics of sequence identity (65% to less than 100% to SEQ ID NO: 1) and particular substitutions (X99F + X101L+ at least one additional substitution selected from X3T, X97D, X103T, X104I, X127I, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X175I, X176S, X194P, and X215K), as well as functional characteristics of activity, specifically where the variant has polyester degrading activity and, optionally, protease activity.
Applicants submit that in the specification of the present application, extensive variant tables are provided identifying amino acid substitutions at various positions. Applicants submit that furthermore, the Examples include multiple engineered variants with structural characteristics as recited in the claims, which variants were further tested for the recited polyester degrading activity.
As noted above, the claims of the application recite both structural and functional characteristics of the recited variants. It is respectfully submitted that not only does the specification describe such functionality, but the specification provides clear guidance to one of skill in the art with respect to how such functionality is structurally achieved.
The claimed variants are anchored to the identity to SEQ ID NO: 1. The specification identifies specific positions that may be modified, while maintaining or improving activity. Such described positions are not arbitrary selections, but reflect targeted engineering of regions relevant to substrate interaction and catalytic performance.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
In response to applicants submission that the claims do not recite all variants with 60% identity to less than 100% identity to SEQ ID NO: 1, but recite all such variants that possess the further recited structural (sequence identity + specific positional modifications) and functional (polyester degrading activity) characteristics, the scope of the claims is acknowledged. Applicants amended claim(s) 1-8 and 13 are directed to all protease variants having a sequence identity of a mere 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2.
In response to applicants submission that in the specification of the present application, extensive variant tables are provided identifying amino acid substitutions at various positions as well as examples which include multiple engineered variants with structural characteristics as recited in the claims, which variants were further tested for the recited polyester degrading activity, while these are acknowledged, it remains that these are insufficient to describe the breadth of the genus of protease variants claimed.
In response to applicants submission that the claimed variants are anchored to the identity to SEQ ID NO: 1 and the specification identifies specific positions that may be modified; while maintaining or improving activity, this is insufficient to adequately describe the vase breadth of the encompassed protease variants.
Claim(s) 1-8, 13, 17 and 18 remain directed to all protease variants having a sequence identity of a mere 65%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, encompassed by these claims.
Given the breadth of the claimed genus of protease variants and the lack of sufficient representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 1-8, 13, 17 and 18 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that protease variant of SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, does not reasonably provide enablement for all possible protease variant having a sequence identity of at least 65%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
This rejection was stated in the previous office action as it applied to previous claims 1-8 and 13. In response applicants have amended claim 1 and traverse the rejection as it applies to newly amended claims 1-8, 13, 17 and 18. Claims 17 and 18, which were left out of the previous rejection due to a typographical mistake, are included for the same reasons stated for claim 1 from which they depend.
Applicants traverse the rejection on the basis that consideration should be given taking into account that the claim language has been amended to recite a sequence identity of at least 65% to SEQ ID NO: 1, but less than 100% identity.
Applicants submit that the specification teaches one of skill in the art how to make the claimed variants. Applicants submit that the specification provides description of variants that possess specific residue positions for modification, as well as lists of additional possible modifications, including lists of combinations of modifications. Applicants submit that the application, particularly in the examples, further includes description of techniques for producing variants, in addition to standard, well-known molecular biology techniques for producing variants. Applicants submit that the particularly provided are exemplary procedures at page 77, line 10 to page 79, line 19, followed by Examples 1-4 and that, accordingly, making variants within the scope of the present claims, in view of such disclosure and knowledge in the art, would be well within the ability of a person of ordinary skill in the art.
Applicants submit that once such variants have been generated, it is also within the abilities of one of skill in the art to identify variants that possess the recited functionality of polyester-degrading activity, as well as optional additional protease activity. Specifically, the application provides assays for measuring polyester degradation, description of experimental conditions, and comparative data demonstrating activity of multiple variants. The examples section of the application is particularly instructive in this regard, particularly, again the procedures described at page 77, line 10 to page 79, line 19 and in Examples 1-4. This section also demonstrates successful identification of active variants with recited physical characteristics, with varied substitutions and described improvement factors.
Applicants submit that in view of the above, it is respectfully submitted that practice of the claimed invention does not require undue experimentation. In consideration of the In re Wands factors, as asserted by the examiner, applicants respectfully provide the following: the quantity of experimentation required is limited, as specific positions and substitutions with defined options are provided ; the amount of guidance provided is substantial, as the application contains lists of substitutions, lists of variants, rationale for structural modifications, and assay methods to determine functional characteristics of resultant variants; there are numerous working examples present, particularly Examples 1-4, in which multiple variants are generated in each Example; the predictability of generated variants is guided by the extensive disclosure of the application; and the breadth of the claims is supported by the disclosure, as detailed herein.
Applicants submit that with regard to the examiner’s statements regarding the invention and the knowledge in the field, it is respectfully submitted that, though the invention related to the field of protein engineering, the specification provides guidance to narrow the scope of what is encompassed by the present application. The invention is directed to guided mutations at defined positions, not all possible mutations and not arbitrary mutations. Applicants submit that the specification provides data demonstrating generation of variants with the recited functionality, across multiple variants.
Applicants amendment of the claims and applicants complete argument is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
Applicants amendment of the claims is acknowledged. Claim(s) 1-8 and 13 continue to be drawn to all possible protease variants having a sequence identity of at least 60%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2.
In response to applicants submission that the specification teaches one of skill in the art how to make the claimed variants and applicants specification provides description of variants that possess specific residue positions for modification, as well as lists of additional possible modifications, as shown in applicants Examples, this is not found persuasive given the extreme breadth of applicants claimed genus of protease variants.
While methods to produce variants of a known sequence such as site-specific mutagenesis, random mutagenesis, etc. are well known to the skilled artisan, producing variants useful as a protein having polyester degrading activity and/or protease activity requires that one of ordinary skill in the art know or be provided with guidance for the selection of which of the infinite number of variants have the activity. Without such guidance one of ordinary skill would be reduced to the necessity of producing and testing all of the virtually infinite possibilities. For the rejected claims would clearly constitute undue experimentation. Guo et al. (H. Guo et al., "Protein Tolerance to Random Amino Acid Change", PNAS 101(25): 9205-9210, June 2004) teach that the percentage of random single substitution mutations which inactivate a protein for the protein 3-methyladenine DNA glycosylase is 34% and that this number appears to be consistent with other studies in other proteins as well. Guo et al. further show in Table 1 that the percentage of active mutants for multiple mutants appears to be exponentially related to this by the simple formula (.66)x X 100% where x is the number of mutations introduced. Applying this estimate to the instant protein 65% identity allows up to 94 mutations within the 269 amino acids of SEQ ID NO:1 and thus only (.66)94 X 100% or 1.08 x 10-17% of random mutants having 65% identity would be active. Current techniques (i.e., high throughput mutagenesis and screening techniques) in the art would allow for finding a few active mutants within several hundred thousand or up to about a million inactive mutants as is the case for the claims limited to 95% identity (despite even this being an enormous quantity of experimentation that would take a very long time to accomplish) but finding a few mutants within several billion or more as in the claims to 65% or less identity would not be possible. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed. Such guidance has not been provided in the instant specification.
The specification does not support the broad scope of the claims which encompass any possible protease variant having a sequence identity of at least 65%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2, because the specification does not establish: (A) regions of the protease which may be modified effecting the protease and/or polyester degrading activity; (B) the general tolerance of proteases to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of protease with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required protease and/or polyester degrading activity and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see, Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those protease variants of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any protease variant having a sequence identity of at least 65%, but less than 100%, to SEQ ID NO:1; wherein the variant comprises the substitutions X99F and X101L; wherein the variant further comprises at least one substitution selected from the group consisting of X3T, X97D, X103T, X1041, X1271, X161W, X161R, X161Y, X161L, X161V, X163R, X172K, X174G, X174V, X175A, X175Y, X175D, X175T, X175V, X1751, X176S, X194P, and X215K; wherein the variant has polyester degrading activity and, optionally, protease activity; and wherein position numbers are based on the numbering of SEQ ID NO:2. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those protease variants having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Closest Prior Art:
US 6,946,128 discloses a subtilisin protease comprising substitutions at positions 99, 101 and 215 relative to SEQ ID NO:2, but does not teach said substitutions in the background of SEQ ID NO:1.
Remarks
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (571) 272-0956. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
8/7/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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